PROJECT SUMMARY Despite recent progress, it is unclear how progranulin deficiency leads to development of the neurodegenerative disease frontotemporal lobar degeneration (FTLD). Progranulin is cleaved into individual granulin peptides that are bioactive and may functionally oppose the progranulin holoprotein. Many believe that progranulin deficiency equally depletes progranulin and granulin levels yet it may be that progranulin deficiency results in a relative excess of granulins compared to progranulin. Little is known about granulin function and no granulin receptor has been identified. The major focus of my research group is to utilize model organisms to understand progranulin function. In this proposal, our objective is to identify the granulin receptor and to determine the normal function of granulins as they relate to organismal stress response. Our central hypothesis is that relative excess of granulins is harmful because granulins impair stress resistance. This hypothesis is based on our observations that in C. elegans 1) heat stress stimulates progranulin cleavage, and 2) expression of individual granulins impairs stress resistance. These clear and reproducible stress phenotypes allow us to take advantage of the genetic tractability of C. elegans to screen for the granulin receptor and understand relative granulin and progranulin function. The rationale for our work is that better understanding of granulin function will lead to better understanding of FTLD disease mechanism and lead to new targets for drug therapy. Our first aim is to identify the granulin receptor(s) and downstream mediators of granulin function. We have an assay of granulin biological activity that we can use to screen for the granulin receptor. Our second aim is to test the model that progranulin and granulins reciprocally modulate stress response. We will do so by expressing different levels of progranulin and granulin in C. elegans and measuring their effect on stress resistance. These studies are significant because in order to truly understand progranulin function and the consequences of progranulin replacement therapy, one must also understand the normal biological properties of both progranulin and granulins. The proposed research is innovative, in our opinion, because it seeks to directly implicate granulin excess, instead of progranulin deficiency, as the driving force in neurodegeneration-related to progranulin mutations. When these studies are successfully completed, expected outcomes are identification of the granulin receptor, insight into the normal function of granulins, and clarity regarding the relative roles of progranulin and granulin in modulating stress resistance. Better understanding of progranulin and granulin function will have several positive impacts, including identification of novel targets for drug therapy and understanding of potential negative consequence of progranulin replacement strategies. Findings from these studies can be rapidly translated to vertebrate models in order to develop new therapies for neurodegenerative diseases.